Catheter-based electroporation (EPo) using monophasic pulses was first employed with cardiac tissue in the 1980s but it was found to be associated with negative side effects such as the induction of an electrically isolating “vapor globe” resulting in a spark (arcing), followed by an explosion and damaging pressure waves ^[14][15][38][44,45,46]. Serious complications such as barotrauma and a pro-arrhythmic effect saw voltage-based energy systems superseded by RF ablation ^[38][39][46,47]. However, Ahsan et al. demonstrated that the cautious use of electroporation at lower energies could successfully avoid arcing and produce sufficient therapeutic lesions ^[40][48]. Modern voltage-based systems typically employ pulsed electric fields (PEFs) ^[41][42][49,50]. Ablation based on EPo is growing in popularity as an alternative to thermal ablation and causes a biophysical phenomenon to arise following the application of PEF ^[2][16][2,51]. These electric fields induce irreparable pore formation in cell membranes [3]. As a result, so-called PFA is considered minimally thermal and creates more predictable and controllable lesions, with minimal interaction with blood flow.

Since 2005, both irreversible (IRE) and reversible (RE) EPo has received considerable attention as a method of disrupting cell membranes for drug delivery or inducing selective cell death, respectively ^[43][11]. Both IRE and RE have the potential to be tissue-specific in terms of lethal or effective thresholds, with extracellular and endothelial structures commonly remaining intact following exposure to electric fields ^[44][17][52,53]. The permanent opening of nanopores in cell membranes activates intracellular molecular pathways, increases ionic and molecular transport, resulting in an overall disruption of the cell membrane and intracellular homeostasis ^[43][45][46][11,21,54]. Exposure to sufficiently large field strength results in IRE, and permanent damage and cell death ensues due to localized rearrangement within membrane structures, while supporting structures remain unscathed ^{[9][47][48][18][19]}[9,55,56,57,58]. RE, in contrast, only transiently opens membrane pores, maintaining cell viability, and is commonly employed in the targeted delivery of drugs and nucleotides ^[43][11].

The extent and targeting of ablation with IRE can be controlled at least to some degree by changing parameters such as pulse amplitude, frequency, duration of the application and pulse number ^[2][20][2,59]. The lethal thresholds for many cell types have been reported based on these parameters; however, many contradictory data exist as it is still an active area of ongoing research. On the face of it, short exposures and microsecond EPo impulses can be used for biomedical applications aimed at drug delivery and gene transfer, while more prolonged impulses are related to cellular injury and ablation by IRE ^[47][49][50][55,60,61]. The shape of the applied pulse is an under-explored, and in many cases a poorly documented, parameter that has not received the same degree of experimental testing as amplitude, frequency and others (Table 1 and Table 2). Using a lung cell line, Kotnik et al. demonstrated that of the parameters used to describe pulse shape, the major factor determining electropermeabilization was the amount of time the pulse amplitude exceeded a certain threshold value ^[51][62]. They suggest that any differences observed between various pulse shapes may in fact be reflecting the difference in time the pulse is above the critical threshold for that cell type. Meanwhile, Stankevic et al. reported that it is the pulse shape and total energy input that contribute to the efficiency of IRE ^[52][63]. Sano et al. (2017) reported that asymmetric waveforms have significantly lower IRE thresholds compared to equivalent symmetrical waveforms, at least for neuroblastoma cells in vitro ^[53][64]. Both symmetrical and asymmetrical biphasic pulses have proven effective in IRE cardiac ablation procedures in both animals and a small number of pilot human trials ^{[15][54][55][21][56]}[45,65,66,67,68]. Overall, asymmetric waveforms appear to produce more effective pore opening than symmetric pulses, possibly due to the different amplitudes of their phases. We recommend that all elements of pulse profile need to be reported, according to a set of recommended guidelines, as the extent that pulse shape contributes towards the safety and efficacy for AF treatment with IRE is unclear ^[57][69]. Overall, this is an area that requires substantial and more fundamental research before it can become part of standard clinical application ^[21][67].